Glucose metabolism is the major energy-producing pathway in the brain. Changes in cerebral glucose uptake (CGU, which reflects delivery, transport and metabolism) have been reported for several neurodegenerative diseases. However, a simple imaging approach to repeatedly and safely assess CGU as part of general daily clinical practice in most hospitals is not available. Our overall goal is to develop and optimize a novel MRI method to detect changes in CGU with the goal of future translation to the clinical assessment of neurodegenerative diseases. To demonstrate the approach, we propose to develop and validate it on Alzheimer?s disease (AD) mouse models. AD is the most common cause of dementia, and currently, more than five million people have AD in the US alone. The etiology of Alzheimer?s disease is unknown, and therapies also are not available. The accumulation of neurotic plaques (A?) and neurofibrillary tangles (NFT), as well as the widespread gliosis, loss of synapses, and the degeneration of neurons, are the major histopathological hallmarks of AD. A diagnosis of AD in the early stages of dementia cannot be determined simply by the amyloid imaging, because many healthy older adults with brain A? deposits never develop dementia in life. Many histological studies have confirmed that the neuronal degeneration is a stronger predictor of dementia than AD pathology. The glucose hypometabolism, which correlates well with cognitive impairment, may be an upstream event of AD. Thus, AD represents a disease model that would benefit better from the CGU measurement. We recently made one exciting discovery that the water frequency can be shifted by the glucose uptake after intravenous glucose infusion. This new finding allows us measure glucose uptake in brain with much higher sensitivity comparing to other MRI methods. Here, we will develop a new jump-return MRI technique that can measure the water frequency shift with highly sensitivity, which allows us measure glucose uptake in brain with much lower glucose concentration. The optimized jump-return MRI method will be applied on two Alzheimer's disease mouse models to verify that the technique is sensitive enough to detect the impaired glucose uptake in brain comparing to the wild type mice. Upon the successful completion of this proposal, we anticipate developing a new clinic-ready MRI technique and a new MRI biomarker that detect and evaluate the Alzheimer's disease associated neuronal degeneration.